WO2022051443A1 - Préparation d'analogues de rbc (nrbc) nucléés destinés à être utilisés en tant que témoins de référence d'hématologie dans des analyseurs d'hématologie automatisés - Google Patents

Préparation d'analogues de rbc (nrbc) nucléés destinés à être utilisés en tant que témoins de référence d'hématologie dans des analyseurs d'hématologie automatisés Download PDF

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WO2022051443A1
WO2022051443A1 PCT/US2021/048778 US2021048778W WO2022051443A1 WO 2022051443 A1 WO2022051443 A1 WO 2022051443A1 US 2021048778 W US2021048778 W US 2021048778W WO 2022051443 A1 WO2022051443 A1 WO 2022051443A1
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red blood
days
blood cells
cells
hours
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PCT/US2021/048778
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Beena LEE
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Bio-Rad Laboratories, Inc.
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Priority to EP21865080.2A priority Critical patent/EP4208021A1/fr
Priority to CN202180054645.1A priority patent/CN116097093A/zh
Publication of WO2022051443A1 publication Critical patent/WO2022051443A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/1012—Calibrating particle analysers; References therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/1031—Investigating individual particles by measuring electrical or magnetic effects
    • G01N15/12—Investigating individual particles by measuring electrical or magnetic effects by observing changes in resistance or impedance across apertures when traversed by individual particles, e.g. by using the Coulter principle
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5094—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for blood cell populations
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/01—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials specially adapted for biological cells, e.g. blood cells
    • G01N2015/012—Red blood cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1006—Investigating individual particles for cytology
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/1012—Calibrating particle analysers; References therefor
    • G01N2015/1014—Constitution of reference particles
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1019—Associating Coulter-counter and optical flow cytometer [OFC]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1024—Counting particles by non-optical means
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1028—Sorting particles
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N2015/1493—Particle size
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/76—Assays involving albumins other than in routine use for blocking surfaces or for anchoring haptens during immunisation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2496/00—Reference solutions for assays of biological material
    • G01N2496/05—Reference solutions for assays of biological material containing blood cells or plasma
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2496/00—Reference solutions for assays of biological material
    • G01N2496/10—Reference solutions for assays of biological material containing particles to mimic blood cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2496/00—Reference solutions for assays of biological material
    • G01N2496/25—Reference solutions for assays of biological material containing added polymers to stabilise biological material against degradation or mantain viscosity or density, e.g. gelatin, polyacrylamides, polyvinyl alcohol

Definitions

  • the early forms of hematology instrumentation have thus been replaced by relatively complex machines that analyze the discrete components of blood based upon the intricate and subtle characteristics of each component.
  • the most recent iteration in automated hematology instrumentation has been the multi-part analysis of human white cells, in addition to the detection of red blood cells and platelets.
  • White cell populations typically include lymphocytes, monocytes, neutrophils, basophiles, and eosinophils.
  • the methods for blood cell analysis involve detection of the electrical and optical properties of each type of blood cell.
  • a typical instrument will count and size red blood cells and platelets independently of the white cell component. To count white cells, it is necessary to destroy the red blood cells using a detergent such as a quaternary ammonium salt, leaving the white cells for counting and sizing.
  • the controls are synthetic suspensions that have the certain physical and chemical characteristics similar to those of blood and that include stable cells or particles whose sizes and shapes closely approximate those of the different cells present in human blood.
  • Hematology reference controls are comprised of RBC, five-part differential WBC, platelet, and nucleated RBC components.
  • Some automated hematology analyzers utilize flow cell fluorescent light scatter to determine cell volume, cell content complexity (i.e. nucleus and granules), and the amount of nucleic acid present in the cells to distinguish different types of nucleated blood cells. Cells with similar cytochemistry properties form a cluster in the graph.
  • NRBC nucleated RBCs
  • NRBCs nucleated RBCs
  • US Patent No.6,221,668 B1 and US Patent No.7,285,417 B2 each of which is hereby incorporated by reference in their entireties.
  • WBCs white blood cells
  • the present invention provides a new process for producing NRBCs of more desirable characteristics, such as optical properties that are distinct from WBCs.
  • the novel NRBCs can be used in hematology reference control products.
  • BRIEF SUMMARY OF THE INVENTION One embodiment of the present invention provides a method for preparing red blood cells from a vertebrate source for use in a hematology blood control product and is suitable for use in a hematology analyzer.
  • the present invention allows for the differentiation between NRBCs and WBC analogs.
  • the claimed process includes these steps: (a) shrinking and washing nucleated red blood cells from a non-human vertebrate by extraction of cellular fluid from the red blood cells; and (b) fixing the cells from step (a) with a fixing agent.
  • An exemplary fixing agent is glutaraldehyde.
  • step (a) of the process further includes incubating the cells at a temperature of about 1 o C to about 22 o C for a time period of about 1 day to about 40 days, about 10 days to about 40 days, or about 20 days to about 35 days.
  • step (a) of the process is performed in the presence of a denaturing agent; and step (b) may further comprise fixing the cells from step (a) at about 1 o C to about 30 o C, about 15 o C to about 25 o C, or about 18 o C to about 22 o C for: up to about 25 hours; about 6 hours to about 36 hours, about 10 hours to about 20 hours, or about 18 to about 24 hours.
  • the present invention relates to modified red blood cells for use as reference controls in automated blood cell analyzers prepared by any one of the processes described in the above paragraphs.
  • the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.
  • a range of 0.1-1.0 represents the terminal values of 0.1 and 1.0, as well as the intermediate values of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges encompassed within 0.1-1.0, such as 0.2-0.5, 0.2-0.8, 0.7-1.0, etc. Values having at least two significant digits within a range are envisioned, for example, a range of 5-10 indicates all the values between 5.0 and 10.0 as well as between 5.00 and 10.00 including the terminal values.
  • the subject invention provides methods for producing hematology analyzer control red blood cell analogs, such as non-human red blood cells shrunken and washed, with the use of a denaturing agent (such as ⁇ -naphthol), and the fixed with the use of a fixative agent (such as glutaraldehyde).
  • a denaturing agent such as ⁇ -naphthol
  • a fixative agent such as glutaraldehyde
  • the process can allow for the production of RBC analogs such that the cellular content is preserved while the optical properties are modified and which permits for the differentiation of the RBC analogs from WBC by automated hematology analyzers.
  • the starting material for the composition of the present invention may be whole blood from a non-human vertebrate, such as any of the common species of chicken.
  • the red blood cells from whole blood of a non-human vertebrate animal are separated from the blood by various methods known in the art such as, for example, by mixing the blood with a solution comprising a polymerized sugar, a salt of a dicarboxylic acid, and a weak base; centrifugation; or, preferably, by allowing the blood to settle for multiple hours at a temperature below room temperature without additional chemicals or forces greater than 1 g.
  • the red blood cells settle at a temperature about about 1 o C to about 25 o C, about 1 o C to about 22 o C, about 1 o C to about 15 o C, or about 2 o C to about 8 o C for at least 1 hour, 2 hours, 4 hours, 12 hours, 24 hours, 36 hours, 48 hours, or greater.
  • the supernatant is then aspirated, leaving the red blood cells.
  • Shrinking of the red blood cells is performed by suspending the cells in a salt solution comprising a denaturing agent, such as those discussed below, and having an osmolality of about 600 to about 1170 mOsm, about 750 to about 1000 mOsm, or about 885 mOsm.
  • the salt solution is, in some embodiments, a hypertonic salt solution that includes naphthol as the denaturing agent, and has a conductivity of about 11600 to about 12000 ⁇ S, about 8000 to about 16000 ⁇ S or about 11800 ⁇ ⁇ S. Since the principle of cell denaturing and shrinking in a hypertonic solution, or one in which the concentration of solutes in the solution is greater than the concentration of solutes in the cell, is a simple one, it is envisioned that any salt can be used as the solute in this step of the invention, so long as it does not cause undue hemolysis or cell association.
  • the salt in the solution can be sodium nitrate, sodium fluoride, potassium nitrate, potassium chloride, sodium chloride, sodium bicarbonate, calcium chloride, potassium sulfate, potassium ferricyanide, potassium cyanide, or combinations thereof.
  • the salt concentration is about 0.1 g/L to about 100 g/L, about 1 g/L to about 10 g/L, or about 2.5 g/L to about 7.5 g/L.
  • naphthol including ⁇ -naphthol and ⁇ -naphthol, can serve as denaturing agents. Other naphthol derivatives are also useful for as denaturing agents in this process.
  • the final concentration of the denaturing agent in the solution can be in a range about 0.1 g/L to about 100 g/L, about 1 g/L to about 10 g/L, about 2.5 g/L to about 7.5 g/L, about 3 g/L to about 6 g/L, or about 4.5 g/L.
  • Examples of commercially available ⁇ -naphthol derivatives that can be used in the present invention include, but are not limited to, 4-chloro-1-naphthol, 1,5- dihydroxynaphthalene, 1,7-dihydroxynaphthalene, 1-methoxy-4-nitronaphtalene, 4- Fluorosulfonyl-1-hydroxy-2-naphthoic acid, 1,3-Dihydroxynaphthalene, 4-methoxy-1- naphthonitrile, 2-nitro-1-naphthol, 4-methoxy-1-naphthol, 2-acetyl-1-naphthol, 9- phenanthrol, 1-naphthol-3,6-disulfonic acid disodium salt hydrate, alpha-hydroxy- heptafluoronaphthalene, 5-amino-1-naphthol, N-(2-Acetamidophenethyl)-1-hydroxy-2- naphthamide
  • metal salts of the naphthols can be used in the subject invention.
  • An especially suitable class of salts for the shrinking step because of their dual role as a dispersing agent and a shrinking agent, are the di-alkali metal salts of the naphthol-disulfonic acids, such as the disodium salt of 1-naphthol-3,6 disulfonic acid.
  • the salt solution has a reagent that has a dispersing effect to prevent undue cell association.
  • Suitable dispersing agents are the di-alkali metal salts of the naphthol-disulfonic acids, and the low molecular weight (less than 42,000) dextrans.
  • the salt solution can further comprise preservatives, such as, for example, EDTA; alcohols such as, for example, ethanol, methyl alcohol, isopropyl alcohol, reagent alcohol (200 proof ethyl alcohol, methyl alcohol, and isopropyl alcohol; Spectrum Chemical Mfg. Corp., New Brunswick, NJ (Catalog No.
  • A1040 methanol, propanol, butanol, pentanol, ethylene glycol, or propylene glycol
  • bases such as, for example, sodium hydroxide, potassium hydroxide
  • acids such as, for example, mercaptosuccinic acid, buffers such as, for example, MOPS and HEPES
  • antimicrobials such as, for example, sodium omadine, amikacin, tetracycline, and gentamycin.
  • Table 1 Salt Solution
  • the red blood cell are suspended in the salt solution for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6, days, 7 days, 8 days, 10 days, 15 days, 20 days, 25 days, 30 days, 35 days, 40 days, or greater at a temperature of at about 0.1 o C to about 22 o C, 1 o C to about 22 o C about 1 o C to about 15 o C, about 1 o C to about 10 o C, or about 2 o C to about 8 o C.
  • MCV mean corpuscular volume
  • the MCV can be reduced by about 1% to about 30%, by about 5% to about 20%, or, preferably, by about8 to about 15%.
  • the incubation of the RBCs in the salt solution can be briefly interrupted to remove the supernatant after at least 1 day, 2 days, or 3 days and the red blood cells are the resuspended in a new salt solution.
  • the red blood cells can be washed by briefly interrupting the incubation as many times as is necessary to obtain a clear supernatant, preferably at least one time. The number of washes can be determined by the presence (or lack thereof) of WBCs in the supernatant.
  • the shrunken and washed RBCs can be resuspended in a fresh salt solution in preparation for the fixing step.
  • the red blood cells can be in a concentration of at least about 1x10 4 cells/ ⁇ L, 1x10 5 cells/ ⁇ L, 5x10 5 cells/ ⁇ L, 1x10 6 cells/ ⁇ L, 1x10 7 cells/ ⁇ L, or greater.
  • the red blood cells obtained following the shrinking and washing steps are further treated with a fixing agent such as, for example, glutaraldehyde, formaldehyde, acetaldehyde, succindialdehyde, or glyoxal.
  • fixing of the red blood cells is accomplished by contacting the suspension of the cells with a solution of glutaraldehyde.
  • the glutaraldehyde may be added in concentrations anywhere from about 5% to about 50%, about 10% to about 40%, or about 24% by weight, so long as the final concentration thereof is in the range of from about 0.01% to about 10%, about 0.1% to about 1%, or about 0.24% to about 0.48% by weight.
  • the RBC and salt solution can be added to the fixative agent solution at a concentration of about 1 ⁇ L/mL to about 100 ⁇ L/mL, about 5 ⁇ L/mL to about 50 ⁇ L/mL, or about 10 ⁇ L/mL.
  • the fixative solution is mixed with red bloods cells by rapidly swirling.
  • the fixative agent and red blood cell mixture can then be incubated at room temperature (about 18 o C to about 22 o C) for a time period of about 6 hours to about 36 hours, about 8 hours to about 24 hours, or about 12 hours to about 16 hours.
  • the fixative agent and red blood cell mixture is incubated in the dark or low- light conditions.
  • the fixed cells are thereafter centrifuged, separated, washed with a buffered solution, and placed in a storage solution.
  • the cells can be washed using a buffered solution by centrifugation, removal of supernatant, and resuspension in the buffered solution.
  • the buffered washing solution should be neutral to alkaline, preferably in the pH range of from about 7.0 to about 10.0.
  • a preferred set of buffering reagents includes sodium hydroxide, potassium chloride, and sodium chloride.
  • An example of a buffered solution for use in the subject invention is M-Ringer’s buffer (Table 2).
  • the RBCs should be washed with the buffered solution as many times as is necessary to obtain a clear supernatant, preferably at least three times.
  • the RBCs can be suspended in any of a variety of storage solutions, including hypotonic, isotonic, or hypertonic solutions relative to a vertebrate body fluid.
  • Isotonic aqueous liquids i.e., those that have the same osmotic pressure as the fluid in a vertebrate, are preferred since they are most compatible with the final blood control product.
  • Conventional additives can be added for the same purposes that they serve in standard cell suspensions of the prior art.
  • the storage solution in which the cells are suspended may be virtually any fluid, including mere water, which does not have a deleterious effect on the fixed cells, such as causing hemolysis, cell association or biodegradation.
  • a preferred storage solution is basically the same buffered solution used in the washing step with the addition of a bactericidal or bacteriostatic agent, to prevent contamination, and a dispersing agent.
  • the bactericidal or bacteriostatic agent can be any known agent added in sufficient concentration to reduce or check bacterial growth.
  • An inexpensive and preferred bactericidal/bacteriostatic agent is gentamicin and/or Proclin 150.
  • Another is the hydrochloride salt of tetracycline. Each may be added in a concentration of about 0.1 grams per liter.
  • the dispersing agent may be one dialkali metal salt of a naphthol-sulfonic acid dextrose, added in a concentration of about 1 gram per liter.
  • a di-alkali metal salt of a naphthol-sulfonic acid such as the dipotassium salt of 2-Naphthol 6,8-disulfonic acid
  • the preferred concentration is from about 0.02 to about 0.05, preferably about 0.04 molar.
  • An example of a storage solution for use in the subject invention is suspension media 23 (Table 3).
  • the cell population or density may be adjusted by any known dilution or concentration technique. For example, if the product shows a density of 300,000 cells per cubic millimeter, and the desired density is about 75,000, the fluid suspension should be diluted by adding three volumes of diluent to obtain the desired density.
  • the instant application provides a method of using a reference control containing the modified red blood cell component disclosed herein.
  • the method comprises the steps of providing a reference control containing the modified red blood cell component disclosed herein; providing a blood analyzer adapted for analyzing the reference control containing the modified red blood cell component; passing the reference control through said blood analyzer for detection of said modified red blood cell component; and reporting the modified red blood cell component in said reference control.
  • the differentiation of the modified red blood cells from other cell types can be obtained using impedance, or optical measurement, or combination thereof.
  • the optical measurement can be fluorescence, light scatter, axial light loss measurements, or combination thereof.
  • Glutaraldehyde was then mixed with the Salt Solution containing the chicken RBCs at a concentration of about 5 x 10 5 cells/ ⁇ L to achieve a glutaraldehyde concentration of between about 0.24% and 0.48%, mixed and incubated for 1-2 days, the glutaraldehyde, Salt Solution, and chicken RBC mixture was centrifuged, and the supernatant was removed. The chicken RBCs were washed by suspending the cells in M-Ringer’s Buffer and centrifuged. The supernatant was removed. The washing step with M-Ringer’s Buffer was repeated. After the final wash with M-Ringer’s Buffer and removal of the supernatant, the chicken RBCs were suspended in Suspension Media.
  • the chicken RBC and Suspension Media mixture was then diluted using Sysmex DCL Diluent and the RBC cell number, MCV, %Eosinophil (Eos), and WBC/RBC% were determined.
  • WBC and NRBC analogs were analyzed on a Sysmex XN10 hematology analyzer.
  • the NRBC analogs and the WBC analogs were displayed on Sysmex XN10 hematology analyzer (FIG.1).

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Abstract

La présente invention a trait à des compositions de nouveaux analogues de globules rouges qui peuvent être distingués des globules blancs dans un instrument hématologique et des procédés de fabrication de tels analogues. Les procédés de création des compositions consistent à laver, à réduire la taille et à fixer des cellules à des températures inférieures ou égales à la température ambiante.
PCT/US2021/048778 2020-09-03 2021-09-02 Préparation d'analogues de rbc (nrbc) nucléés destinés à être utilisés en tant que témoins de référence d'hématologie dans des analyseurs d'hématologie automatisés WO2022051443A1 (fr)

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EP21865080.2A EP4208021A1 (fr) 2020-09-03 2021-09-02 Préparation d'analogues de rbc (nrbc) nucléés destinés à être utilisés en tant que témoins de référence d'hématologie dans des analyseurs d'hématologie automatisés
CN202180054645.1A CN116097093A (zh) 2020-09-03 2021-09-02 制备有核rbc(nrbc)类似物用作自动化血液分析仪中的参比血液对照

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